tbuckley/cabot-search huggingface dataset:
Assessment of Clinical Worsening End Points as a Surrogate for Mortality in Pulmonary Arterial Hypertension: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Authors: Élodie Tremblay, Camille Gosselin, Vicky Mai, Annie C. Lajoie, Roubi Kilo, Jason Weatherald, Yves Lacasse, Sebastien Bonnet, Jean-Christophe Lega, Steeve Provencher
Journal: Circulation (2022)

Background: Clinical worsening (CW) is a composite end point commonly used in pulmonary arterial hypertension (PAH) trials. We aimed to assess the trial-level surrogacy of CW for mortality in PAH trials, and whether the various CW components were similar in terms of frequency of occurrence, treatment-related relative risk (RR) reduction, and importance to patients. Methods: We searched MEDLINE, Embase, and the Cochrane Library (January 1990 to December 2020) for trials evaluating the effects of PAH therapies on CW. The coefficient of determination between the RR for CW and mortality was assessed by regression analysis. The frequency of occurrence, RR reduction, and importance to patients of the CW components were assessed. Results: We included 35 independent cohorts (9450 patients). PAH therapies significantly reduced CW events (RR, 0.64 [95% CI, 0.55–0.73]), including PAH-related hospitalizations (RR, 0.61 [95% CI, 0.47–0.79]), treatment escalation (RR, 0.57 [95% CI, 0.38–0.84]) and symptomatic progression (RR, 0.58 [95% CI, 0.48–0.69]), and modestly reduced all-cause mortality when incorporating deaths occurring after a primary CW-defining event (RR, 0.860 [95% CI, 0.742–0.997]). However, the effects of PAH-specific therapies on CW only modestly correlated with their effects on mortality ( R 2 trial , 0.35 [95% CI, 0.10–0.59]; P &lt;0.0001), and the gradient in the treatment effect across component end points was large in the majority of trials. The weighted proportions of CW-defining events were hospitalization (33.5%) and symptomatic progression (32.3%), whereas death (6.7%), treatment escalation (5.6%), and transplantation/atrioseptostomy (0.2%) were infrequent. CW events were driven by the occurrence of events of major (49%) and mild-to-moderate (37%) importance to patients, with 14% of the events valued as critical. Conclusions: PAH therapies significantly reduced CW events, but study-level CW is not a surrogate for mortality in PAH trials. Moreover, components of CW largely vary in frequency, response to therapy, and importance to patients and are thus not interchangeable. Registration: URL: https://www.crd.york.ac.uk/PROSPERO ; Unique identifier: CRD42020178949.
Deformation of Transcatheter Aortic Valve Prostheses: Implications for Hypoattenuating Leaflet Thickening and Clinical Outcomes
Authors: Miho Fukui, Vinayak N. Bapat, Santiago Garcia, Marshall W. Dworak, Go Hashimoto, Hirotomo Sato, Mario Gössl, Maurice Enriquez-Sarano, John R. Lesser, João L. Cavalcante, Paul Sorajja
Journal: Circulation (2022)

Although transcatheter aortic valve replacement (TAVR) therapy continues to grow, there have been concerns about the occurrence of hypoattenuating leaflet thickening (HALT), which may affect prosthesis function or durability. This study aimed to examine prosthesis frame factors and correlate their extent to the frequency of HALT and clinical outcomes.We prospectively examined 565 patients with cardiac computed tomography screening for HALT at 30 days after balloon-expandable SAPIEN3 and self-expanding EVOLUT TAVR. Deformation of the TAVR prostheses, asymmetric prosthesis leaflet expansion, prosthesis sinus volumes, and commissural alignment were analyzed on the postprocedural computed tomography. For descriptive purposes, an index of prosthesis deformation was calculated, with values >1.00 representing relative midsegment underexpansion. A time-to-event model was performed to evaluate the association of HALT with the clinical outcome.Overall, HALT was present in 21% of SAPIEN3 patients and in 16% of EVOLUT patients at 30 days after TAVR. The occurrence of HALT was directly associated with greater prosthesis frame deformation (P<0.001), worse asymmetry of the leaflets (P<0.001), and smaller TAVR neosinus volumes (P<0.001). These relations were present in both prosthetic types and in all of their size ranges (all P<0.05). In multivariable analyses that include clinical variables previously associated with HALT (eg, anticoagulant therapy), variables of TAVR prosthesis deformation remained predictive of HALT. Although HALT was not associated with changes in prosthetic hemodynamics, its presence was associated with the risk of mortality at 1 year, with respect to greater incidences of all-cause mortality (hazard ratio, 2.98 [95% CI, 1.57-5.63]; P=0.001), cardiac death (hazard ratio, 4.58 [95% CI, 1.81-11.6]; P=0.001), and a composite outcome of all-cause mortality and heart failure hospitalization (hazard ratio, 1.94 [95% CI, 1.14-3.30]; P=0.02) with adjustment for age, sex, and comorbidities.Nonuniform expansion of TAVR prostheses resulting in frame deformation, asymmetric leaflet, and smaller neosinus volume is related to occurrence of HALT in patients who undergo TAVR. These data may have implications for both prosthesis valve design and deployment techniques to improve clinical outcomes for these patients.
Restoration of Cardiomyogenesis in Aged Mouse Hearts by Voluntary Exercise
Authors: Carolin Lerchenmüller, Ana Vujic, Sonja Mittag, Annie Wang, Charles P. Rabolli, Chiara Heß, Fynn Betge, Ashraf Y. Rangrez, Malay Chaklader, Christelle Guillermier, Frank Gyngard, Jason D. Roh, Haobo Li, Matthew L. Steinhauser, Norbert Frey, Beverly Rothermel, Christoph Dieterich, Anthony Rosenzweig, Richard T. Lee
Journal: Circulation (2022)

The human heart has limited capacity to generate new cardiomyocytes and this capacity declines with age. Because loss of cardiomyocytes may contribute to heart failure, it is crucial to explore stimuli of endogenous cardiac regeneration to favorably shift the balance between loss of cardiomyocytes and the birth of new cardiomyocytes in the aged heart. We have previously shown that cardiomyogenesis can be activated by exercise in the young adult mouse heart. Whether exercise also induces cardiomyogenesis in aged hearts, however, is still unknown. Here, we aim to investigate the effect of exercise on the generation of new cardiomyocytes in the aged heart.
Modification of the Association Between Frequent Aspirin Use and Ovarian Cancer Risk: A Meta-Analysis Using Individual-Level Data From Two Ovarian Cancer Consortia
Authors: Lauren M. Hurwitz, Mary K. Townsend, Susan J. Jordan, Alpa V. Patel, Lauren R. Teras, James V. Lacey, Jennifer A. Doherty, Holly R. Harris, Marc T. Goodman, Yurii B. Shvetsov, Francesmary Modugno, Kirsten B. Moysich, Kim Robien, Anna Prizment, Joellen M. Schildkraut, Andrew Berchuck, Renée T. Fortner, Andrew T. Chan, Nicolas Wentzensen, Patricia Hartge, Dale P. Sandler, Katie M. O'Brien, Hoda Anton-Culver, Argyrios Ziogas, Usha Menon, Susan J. Ramus, Celeste Leigh Pearce, Anna H. Wu, Emily White, Ulrike Peters, Penelope M. Webb, Shelley S. Tworoger, Britton Trabert
Journal: Journal of Clinical Oncology (2022)

PURPOSE Frequent aspirin use has been associated with reduced ovarian cancer risk, but no study has comprehensively assessed for effect modification. We leveraged harmonized, individual-level data from 17 studies to examine the association between frequent aspirin use and ovarian cancer risk, overall and across subgroups of women with other ovarian cancer risk factors. METHODS Nine cohort studies from the Ovarian Cancer Cohort Consortium (n = 2,600 cases) and eight case-control studies from the Ovarian Cancer Association Consortium (n = 5,726 cases) were included. We used Cox regression and logistic regression to assess study-specific associations between frequent aspirin use (≥ 6 days/week) and ovarian cancer risk and combined study-specific estimates using random-effects meta-analysis. We conducted analyses within subgroups defined by individual ovarian cancer risk factors (endometriosis, obesity, family history of breast/ovarian cancer, nulliparity, oral contraceptive use, and tubal ligation) and by number of risk factors (0, 1, and ≥ 2). RESULTS Overall, frequent aspirin use was associated with a 13% reduction in ovarian cancer risk (95% CI, 6 to 20), with no significant heterogeneity by study design ( P = .48) or histotype ( P = .60). Although no association was observed among women with endometriosis, consistent risk reductions were observed among all other subgroups defined by ovarian cancer risk factors (relative risks ranging from 0.79 to 0.93, all P-heterogeneity &gt; .05), including women with ≥ 2 risk factors (relative risk, 0.81; 95% CI, 0.73 to 0.90). CONCLUSION This study, the largest to-date on aspirin use and ovarian cancer, provides evidence that frequent aspirin use is associated with lower ovarian cancer risk regardless of the presence of most other ovarian cancer risk factors. Risk reductions were also observed among women with multiple risk factors, providing proof of principle that chemoprevention programs with frequent aspirin use could target higher-risk subgroups.
Microbial Burden-associated Cytokine Storm May Explain Nonresolving Acute Respiratory Distress Syndrome in Patients with COVID-19
Authors: Taro Yasuma, Corina N. D’Alessandro-Gabazza, Tetsu Kobayashi, Esteban C. Gabazza, Hajime Fujimoto
Journal: American Journal of Respiratory and Critical Care Medicine (2022)
Addition of the nuclear export inhibitor selinexor to standard intensive treatment for elderly patients with acute myeloid leukemia and high risk myelodysplastic syndrome
Authors: J. J. W. M. Janssen, B. Löwenberg, M. Manz, B. J. Biemond, P. E. Westerweel, S. K. Klein, M. Fehr, H. A. M. Sinnige, A. Efthymiou, M. C. J. C. Legdeur, T. Pabst, M. Gregor, M. W. M. van der Poel, D. Deeren, L. W. Tick, M. Jongen-Lavrencic, F. van Obbergh, R. S. Boersma, O. de Weerdt, Y. Chalandon, D. Heim, O. Spertini, G. van Sluis, C. Graux, G. Stüssi, Y. van Norden, G. J. Ossenkoppele
Journal: Leukemia (2022)
Brentuximab Vedotin Plus AVD for First-Line Treatment of Early-Stage Unfavorable Hodgkin Lymphoma (BREACH): A Multicenter, Open-Label, Randomized, Phase II Trial
Authors: Luc-Matthieu Fornecker, Julien Lazarovici, Igor Aurer, René-Olivier Casasnovas, Anne-Claire Gac, Christophe Bonnet, Krimo Bouabdallah, Pierre Feugier, Lena Specht, Lysiane Molina, Mohamed Touati, Cécile Borel, Aspasia Stamatoullas, Emmanuelle Nicolas-Virelizier, Laurent Pascal, Pieternella Lugtenburg, Nicola Di Renzo, Thierry Vander Borght, Alexandra Traverse-Glehen, Peggy Dartigues, Martin Hutchings, Annibale Versari, Michel Meignan, Massimo Federico, Marc André
Journal: Journal of Clinical Oncology (2022)

The prognosis of patients with early-stage unfavorable Hodgkin lymphoma remains unsatisfactory. We assessed the efficacy and safety of brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (BV-AVD) in previously untreated, early-stage unfavorable Hodgkin lymphoma (ClinicalTrials.gov identifier: NCT02292979). BREACH is a multicenter, randomized, open-label, phase II trial. Eligible patients were age 18-60 years with ≥ 1 unfavorable EORTC/LYSA criterion. Patients were randomly assigned (2:1) to four cycles of BV-AVD or standard doxorubicin, bleomycin, vincristine, and dacarbazine (ABVD), followed by 30 Gy involved node radiotherapy. The primary end point was the positron emission tomography (PET) response rate after two cycles by expert independent review using the Deauville score. The study was designed to test if the PET-negative rate after two cycles of BV-AVD was superior to 75%. We hypothesized a 10% increase in the PET-negative rate after two cycles of BV-AVD. Between March 2015 and October 2016, 170 patients were enrolled. After two cycles, the primary end point of the study was met: 93 (82.3%; 90% CI, 75.3 to 88.0) of 113 patients in the BV-AVD arm were PET-negative (Deauville score 1-3) compared with 43 (75.4%; 90% CI, 64.3% to 84.5%) of 57 in the ABVD arm. The 2-year progression-free survival (PFS) was 97.3% (95% CI, 91.9 to 99.1) and 92.6% (95% CI, 81.4% to 97.2%) in the BV-AVD and ABVD arms, respectively. High total metabolic tumor volume was associated with a significantly shorter PFS (hazard ratio, 17.9; 95% CI, 2.2 to 145.5; P < .001). For patients with high total metabolic tumor volume, the 2-year PFS rate was 90.9% (95% CI, 74.4 to 97.0) and 70.7% (95% CI, 39.4% to 87.9%) in the BV-AVD and ABVD arms, respectively. BV-AVD demonstrated an improvement in the PET-negative rate compared with ABVD after two cycles.
Phase II LEAP-004 Study of Lenvatinib Plus Pembrolizumab for Melanoma With Confirmed Progression on a Programmed Cell Death Protein-1 or Programmed Death Ligand 1 Inhibitor Given as Monotherapy or in Combination
Authors: Ana Arance, Luis de la Cruz-Merino, Teresa M. Petrella, Rahima Jamal, Lars Ny, Ana Carneiro, Alfonso Berrocal, Ivan Márquez-Rodas, Anna Spreafico, Victoria Atkinson, Fernanda Costa Svedman, Andrew Mant, Muhammad A. Khattak, Catalin Mihalcioiu, Sekwon Jang, C. Lance Cowey, Alan D. Smith, Natalyn Hawk, Ke Chen, Scott J. Diede, Clemens Krepler, Georgina V. Long
Journal: Journal of Clinical Oncology (2022)

Effective treatments are needed for melanoma that progresses on inhibitors of programmed cell death protein-1 (PD-1) or its ligand (PD-L1). We conducted the phase II LEAP-004 study to evaluate the combination of the multikinase inhibitor lenvatinib and the PD-1 inhibitor pembrolizumab in this population (ClinicalTrials.gov identifier: NCT03776136).Eligible patients with unresectable stage III-IV melanoma with confirmed progressive disease (PD) within 12 weeks of the last dose of a PD-1/L1 inhibitor given alone or with other therapies, including cytotoxic T-cell lymphocyte-associated antigen 4 (CTLA-4) inhibitors, received lenvatinib 20 mg orally once daily plus ≤ 35 doses of pembrolizumab 200 mg intravenously once every 3 weeks until PD or unacceptable toxicity. The primary end point was objective response rate (ORR) per RECIST, version 1.1, by independent central review.A total of 103 patients were enrolled and treated. The median study follow-up was 15.3 months. ORR in the total population was 21.4% (95% CI, 13.9 to 30.5), with three (2.9%) complete responses and 19 (18.4%) partial responses. The median duration of response was 8.3 months (range, 3.2-15.9+). ORR was 33.3% in the 30 patients with PD on prior anti-PD-1 plus anti-CTLA-4 therapy. The median progression-free survival and overall survival in the total population were 4.2 months (95% CI, 3.8 to 7.1) and 14.0 months (95% CI, 10.8 to not reached), respectively. Grade 3-5 treatment-related adverse events occurred in 47 (45.6%) patients, most commonly hypertension (21.4%); one patient died from a treatment-related event (decreased platelet count).Lenvatinib plus pembrolizumab provides clinically meaningful, durable responses in patients with advanced melanoma with confirmed PD on prior PD-1/L1 inhibitor-based therapy, including those with PD on anti-PD-1 plus anti-CTLA-4 therapy. The safety profile was as expected. These data support lenvatinib plus pembrolizumab as a potential regimen for this population of high unmet need.
A prescription from Kerala for transforming healthcare
Authors: Richard Smith
Journal: BMJ (2022)

Many investors are striving to incorporate granular ESG data into their decision-making. The use of scores themselves can be questioned-do they accurately reflect one’s views, or are too many decisions being delegated? Or should one integrate ESG metrics directly into portfolio construction? We take the view of an index provider serving various clients who are looking to systematize their views. The paper naturally has two arcs, the first being score design from the ground up. The second part concerns the use of these scores (and sub-scores) in portfolio construction, wherein both the investing hypothesis and practicalities of data availability are discussed. We recommend that ESG portfolios be checked for unintended factor exposures, ESG metrics performance, as well as traditional backtest measures. In order to focus on techniques, we limit the scope of data and companies being included in this expository survey.
CA-125 KELIM as a Potential Complementary Tool for Predicting Veliparib Benefit: An Exploratory Analysis From the VELIA/GOG-3005 Study
Authors: Benoit You, Vasudha Sehgal, Balakrishna Hosmane, Xin Huang, Peter J. Ansell, Minh H. Dinh, Katherine Bell-McGuinn, Xizhi Luo, Gini F. Fleming, Michael Friedlander, Michael A. Bookman, Kathleen N. Moore, Karina D. Steffensen, Robert L. Coleman, Elizabeth M. Swisher
Journal: Journal of Clinical Oncology (2022)

In VELIA trial, veliparib combined with carboplatin-paclitaxel, followed by maintenance (veliparib-throughout) was associated with improved progression-free survival (PFS) compared with carboplatin-paclitaxel alone in patients with high-grade ovarian carcinomas. We explored the prognostic value of the modeled cancer antigen (CA)-125 elimination rate constant K (KELIM), which is known to be an indicator of the intrinsic tumor chemosensitivity (the faster the rate of CA-125 decline, the higher the KELIM and the higher the chemosensitivity), and its association with benefit from veliparib.Individual KELIM values were estimated from longitudinal CA-125 kinetics. Patients were categorized as having favorable (≥ median) or unfavorable (< median) KELIM. The prognostic value of KELIM for veliparib-related PFS benefit was explored in cohorts treated with primary or interval debulking surgery, according to the surgery completeness, the disease progression risk group, and the homologous recombination (HR) status (BRCA mutation, HR deficiency [HRD], or HR proficiency [HRP]).The data from 854 of 1,140 enrolled patients were analyzed (primary debulking surgery, n = 700; interval debulking surgery, n = 154). Increasing KELIM values were associated with higher benefit from veliparib in HRD cancer, as were decreasing KELIM values in HRP cancer. The highest PFS benefit from veliparib was observed in patients with both favorable KELIM and BRCA mutation (hazard ratio, 0.28; 95% CI, 0.13 to 0.61) or BRCA wild-type HRD cancer (hazard ratio, 0.43; 95% CI, 0.26 to 0.70), consistent with the association between poly (adenosine diphosphate-ribose) polymerase inhibitor efficacy and platinum sensitivity. In contrast, seventy-four percent of patients with a BRCA mutation and unfavorable KELIM progressed within 18 months while on veliparib. The patients with HRP cancer and unfavorable KELIM might have benefited from the veliparib chemosensitizing effect.In addition to HRD/BRCA status, the tumor primary chemosensitivity observed during the first-line chemotherapy might be another complementary determinant of poly (adenosine diphosphate-ribose) polymerase inhibitor efficacy.
Congenital Melanocytic Nevi Syndrome With Leptomeningeal Melanoma
Authors: Ashish Mohite, Archi Agrawal, Nilendu Purandare, Sneha Shah, Ameya Puranik, Sayak Choudhury, Indraja Dev, Suchismita Ghosh, Venkatesh Rangarajan
Journal: Clinical Nuclear Medicine (2022)

The incidence of congenital melanocytic nevi (CMNs) is 1% to 6% for small- to intermediate-size nevi to 1 in 500,000 for giant size nevi. Large and satellite CMNs are known to be associated with neurocutaneous melanosis and central nervous system malformations such as Dandy-Walker malformation, defects of the vertebra-skull, and intraspinal lipomas. We hereby present a case of CMN syndrome in an 18-year-old girl with leptomeningeal melanoma, evaluated with MRI, adequately staged, and screened with FDG PET.
Elevated 68Ga-FAPI Uptake by Primary Benign Intraosseous Meningioma
Authors: Weidong Gong, Xiao Yang, Lanying Li, Jiao Ma, Chunyin Zhang
Journal: Clinical Nuclear Medicine (2022)

Abstract Intraosseous meningioma is an extremely rare benign tumor. We present the 68 Ga–fibroblast activation protein inhibitor (FAPI) PET/CT findings of primary intraosseous meningioma in a 71-year-old woman. 68 Ga-FAPI PET/CT revealed an intraosseous mass in the right parietal bone with increased FAPI activity. Primary skull malignancy was suspected. However, pathological examination after resection of the mass in the right parietal bone confirmed the diagnosis of benign meningioma (WHO I). A final diagnosis of benign intraosseous meningioma was made.
Diplopia Related to a Pediatric Cervical Rhabdoid Tumor in 18F-FDG PET
Authors: Nicolas Jacquet-Francillon, Vincent Habouzit, Loris Besson, Pierre-Benoît Bonnefoy, Nathalie Prevot
Journal: Clinical Nuclear Medicine (2022)

Increased muscle uptake is commonly seen with 18 F-FDG PET/CT because of an important physiological muscle glucose metabolism. Muscle uptake can express a recent significant muscle activity. However, the absence of muscle uptake is almost never described or interpreted. We describe the case of an 8-year-old boy with extrarenal rhabdoid tumor in the right carotid space. An MRI and an 18 F-FDG PET/CT were performed for the diagnostic workup. There was no uptake in the lateral rectus oculomotor muscle unlike all other oculomotor muscles. The ophthalmological examination found a diplopia confirmed by the Lancaster test.
18F-FDOPA and MRI Findings in a Case of Multiple Sclerosis
Authors: François Lersy, Stéphane Kremer, Salvatore Chibbaro, Izzie Jacques Namer, Caroline Bund
Journal: Clinical Nuclear Medicine (2022)

A 39-year-old woman with no significant medical history underwent a brain MRI because of headaches and dysarthria having lasted 3 weeks. A tumor lesion was suspected. PET imaging was decided. She underwent FDG and FDOPA PET, leading to the diagnosis of low-grade glioma. Three months later, a new imaging assessment was organized. It showed a decrease in the hypermetabolism of the lesion and the appearance of a second lesion questioning the diagnosis. Further assessment led to the conclusion of a multiple sclerosis. This case illustrates that FDOPA PET uptake should be interpreted with caution in patients with suspected primary brain tumors.
FDG PET/CT in Unilateral Renal Metastasis From Colon Cancer
Authors: Xia Ji, Aisheng Dong
Journal: Clinical Nuclear Medicine (2022)

Renal metastasis from colon cancer is rare. We describe FDG PET/CT findings in a case with a right renal and a postcaval lymph node metastasis from colon cancer. Both the renal tumor and postcaval lymph node showed increased FDG uptake with SUV max of 6.1 for the renal tumor and 5.5 for the postcaval lymph node. The imaging findings mimicked a primary renal cancer with postcaval lymph node metastasis.